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Nicotine effects on renal function in experimental diabetes

Institution: University of California, San Diego
Investigator(s): Francis Gabbai, M.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0169 Award: $98,313
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Smoking has been recognized as a major risk factor for the development and progression of kidney disease in patients with both insulin dependent and non insulin dependent diabetes mellitus. As a risk factor, smoking 1) increases the risk for the presence of protein in the urine, 2) shortens the time interval between onset of diabetes and onset of presence of protein in the urine, and 3) accelerates the rate at which patients lose kidney function and require dialysis in order to live. In spite of the major impact of smoking in progression of diabetic renal disease, very little is known about the mechanism(s) by which smoking accelerates renal injury. Preliminary studies obtained for this submission demonstrate that intravenous administration of nicotine (as a surrogate for smoking) increases hydrostatic pressure in the kidney filtering unit (glomerulus). This increase in glomerular hydrostatic pressure has been recognized as a major risk factor for the progression of kidney disease in experimental model of diabetes. Since glomerular hypertension is such an important risk factor, this proposal will focus in defining the mechanism(s) by which nicotine increases glomerular pressure. Studies will be directed at analyzing the role of various hormones or mediators including angiotensin II, nitric oxide and renal nerves.

In Specific Aim #1 of this project we will investigate if increased levels of angiotensin II (a major hormone in the kidney) are responsible for the increase in glomerular pressure during nicotine administration. These studies will include measurements of kidney angiotensin II after nicotine administration and studies examining the effects of drugs capable of suppressing angiotensin II generation.

Previous studies in humans and experimental animals have demonstrated that nicotine suppresses the production of an important vasodilator, nitric oxide. In Specific Aim # 2 we will test the hypothesis that nicotine induced glomerular hypertension is secondary to decreased production of nitric oxide. Studies will include measurements of nitric oxide and test examining the capacity of nicotine treated kidneys to respond to agents capable of directly stimulating nitric oxide production.

Nicotine is also known to induce increased adrenergic activity. In Specific Aim #3 we will investigate the role of increased sympathetic activity as a mechanism responsible for increasing angiotensin II activity. These studies will examine the effects of surgical section of the renal nerves (renal denervation) and administration of agents capable of blocking the effects of renal nerves on the renal response to nicotine administration.

The long term goal of this project is to define the mechanism(s) responsible for nicotine induced renal injury and utilize this knowledge to develop specific treatments capable of preventing the deleterious effects of nicotine on progression of kidney disease in smokers.

Final Report
Introduction: Smoking has been recognized as a major risk for the development and the progression of kidney disease in patients with both insulin-dependent and non insulin-dependent diabetes mellitus. As a risk factor, smoking 1) increases the risk for the presence of protein in the urine, 2) shortens the time interval between onset of diabetes and onset of presence of protein in the urine, and 3) accelerates the rate at which patients loss kidney function and require dialysis in order to live. In spite of the major impact of smoking on progression of diabetic renal disease, very little is known about the mechanism(s) by which smoking accelerates kidney injury.

Topic address: These studies were designed to 1) Investigate the effect of intravenous administration of nicotine (as a surrogate for smoking) on kidney function and to define whether nicotine modifies the pressure within the kidney filtering unit (glomerulus) and 2) To test if these changes in intraglomerular pressure can be prevented with the administration of an agent which blocks the effect of angiotensin II (a major kidney hormone). Progression Toward Specific Aims: Studies performed during this period of funding evaluated the effect of nicotine administration in glomerular pressure in normal rats and rats with experimental diabetes. The results of the studies demonstrate that the administration of nicotine increases glomerular pressure both in normal rats and rats with experimental diabetes. These changes in glomerular pressure were independent of changes in systemic blood pressure.

To investigate if the changes in glomerular pressure observed during nicotine administration reflect an increase in the activity in of one of the major renal hormones (angiotensin II) a new set of experiments was designed in which both normal rats and rats with experimental diabetes received losartan, an agent capable of blocking the effect of angiotensin II prior to the administration of nicotine. Results of this subset of experiments revealed that administration of losartan prevented the increase in glomerular pressure both in control animals and in animals with experimental diabetes during administration of nicotine. These findings clearly demonstrate that nicotine alters kidney function by increasing angiotensin II. The increase in angiotensin II observed during nicotine administration may be of critical importance to understand the effects of smoking/nicotine on progression of renal disease in diabetes. Previous studies have clearly established that increases in angiotensin II activity constitute a major risk factor for progression of renal disease. Further increases in angiotensin II secondary to smoking/nicotine could provide an important stimulus for progression of renal disease.

Future direction and Impact: The importance of our present findings that nicotine increases angiotensin II is that the use of commonly prescribed medication for treatment of hypertension and proteinuria, like angiotensin converting enzyme inhibitors or angiotensin II receptor antagonist may prevent smoking/nicotine induced renal damage. Based on the limited success of smoking losartan ,the possibility that a rather benign medication could be used to prevent or retard the effect of smoking/nicotine on renal function provides an extremely attractive alternative therapy.
Publications

Effect of nicotine administration on glomerular hemodynamic in normal rats with experimental diabetes.
Periodical: Journal of American Society of Nephrology Index Medicus:
Authors: Gabbai FB, and Khang SJ ABS
Yr: 2001 Vol: 12 Nbr: Abs: Pg: A253